Activity of Oral ALS-008176 in a Respiratory Syncytial Virus Challenge Study

Abstract

BACKGROUND Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality. There is no known effective therapy. METHODS We conducted a randomized, double-blind, clinical trial in healthy adults inoculated with RSV. Participants received the oral nucleoside analogue ALS-008176 or placebo 12 hours after confirmation of RSV infection or 6 days after inoculation. Treatment was administered every 12 hours for 5 days. Viral load, disease severity, resistance, and safety were measured throughout the 28-day study period, with measurement beginning before inoculation. The primary end point was the area under the curve (AUC) for viral load, which was assessed immediately before administration of the first dose through the 12th day after inoculation in participants infected with RSV. RESULTS A total of 62 participants received placebo or one of three ALS-008176 dosing regimens: 1 loading dose of 750 mg followed by 9 maintenance doses of 500 mg (group 1), 1 loading dose of 750 mg followed by 9 maintenance doses of 150 mg (group 2), or 10 doses of 375 mg (group 3). In the 35 infected participants (23 of whom were treated with ALS-008176), the AUCs for viral load for groups 1, 2, and 3 and the placebo group were 59.9, 73.7, 133.4, and 500.9 log10 plaque-forming-unit equivalents × hours per milliliter, respectively (P≤0.001). The time to nondetectability on polymerase-chain-reaction assay (P<0.001), the peak viral load (P≤0.001), the AUC for symptom score (P<0.05), and the AUC for mucus weight were lower in all groups receiving ALS-008176 than in the placebo group. Antiviral activity was greatest in the two groups that received a loading dose--viral clearance was accelerated (P≤0.05), and the AUC for viral load decreased by 85 to 88% as compared with the placebo group. Within this small trial, no viral rebound or resistance was identified. There were no serious adverse events, and there was no need for premature discontinuation of the study drug. CONCLUSIONS In this RSV challenge study, more rapid RSV clearance and a greater reduction of viral load, with accompanying improvements in the severity of clinical disease, were observed in the groups treated with ALS-008176 than in the placebo group. (Funded by Alios BioPharma; ClinicalTrials.gov number, NCT02094365.).

Genomic Loads and Genotypes of Respiratory Syncytial Virus: Viral Factors during Lower Respiratory Tract Infection in Chilean Hospitalized Infants

“…Recent promising reports on the development of drug therapeutics for RSV have been published [33,34] in response to a critical medical need for the care of infants with moderate to severe RSV illness. In parallel, molecular virology has enhanced our ability to dissect the viral contribution to the severity of the disease.…”

Delivery of ALX-0171 by inhalation greatly reduces respiratory syncytial virus disease in newborn lambs

“…, 57-59 HEp-2 cells were infected in 300 cm 2 flasks at 0.5-1 multiplicity of infection (MOI) at a confluence of 80-90% by applying 4-5 mL of hRSV stock (Memphis 37 hRSV that was used originated from Meridian LifeScience, Memphis, TN, USA). Usually within 48-60 hours, abundant syncytia appeared and close to 100% cytopathic effect was reached (as ascertained by periodic inverted microscope inspections).…”

Respiratory Syncytial Virus: Infection, Detection, and New Options for Prevention and Treatment

“…With regard to RSV therapeutic development, a robust in vitro RSV polymerase system (115,117,351) has been used to test nucleoside analogue libraries and other small-molecule inhibitors for their ability to inhibit the RSV polymerase complex. There is one nucleoside analogue named ALS-008176 (4=-chloromethyl-2=-deoxy-3=,5=-di-O-isobutyryl-2=-fluorocytidine) that was discovered using an RSV replicon readout system (352); it underwent successful clinical trials and was reported to inhibit RSV viral load by over 85% in human volunteers (102). Successful clinical trials are not a guarantee of safety, however.…”